Thursday, July 11, 2013

Melzack & Katz, Pain. Part 14e: The stars in our heads

The paper, Pain


Most recent blogposts:

Part 14: Side trip out to the periphery! Part 14b: Prevention of pain neurotags is WAY easier than cure Part 14cPW Nathan was an interesting pain researcher  Part 14dBrain glia are from neuroectoderm and PNS glia are from neural crest


SEE ALL PREVIOUS BLOGPOSTS IN THIS SERIES LISTED AT THE END

Today, still fogbound but safe at anchor on our little island [in the middle of some vast stretch of river we're traveling along, the dimensions of which at the moment we have no clue], we need to consider and discuss astroglia for at least one post. 

So, we are back inside the CNS again, completely inside the neural tube derivatives, completely, with only and all the descendants of neuroectoderm. [Nothing whatever to do with neural crest now.]  

I don't know for a fact that Melzack ever considered astroglia, or any other brain cell type, for that matter, specifically: my guess is he probably did; he seems like someone who would consider everything in due course, but then would move on because his quest was for comprehending the big picture. Many researchers are out there madly decoding what astroglia do in the spinal cord, in the dorsal horn, where nociceptive input first becomes stalled, which is reassuring... let's look where these weird and wonderful cells come from. 

Once upon a time
In the beginning was (and still is) the neural stem cell. It is the primal cell from which all other brain cells are born. [Except for microglia. They slip in there early, before the neural tube/CNS closes up, and live their own lives as immune cells. The brain "needs" them, I suppose, or else evolution would likely not have permitted their existence inside the brain.. but I digress.] 


CNS cell fates, p. 24 source
In a developing central nervous system, inside this tube, there are all these baby cells, struggling to survive, their feet in the tube's wall and their heads out in the tube's interior (that's how I picture them anyway, little arms up in the air hoping to be picked up from their little cribs..). Whether they survive or not depends a lot on their own little local environment.


"Vertebrate proneural genes are often expressed in restricted progenitor domains and are implicated in the specification of neuronal subtypes. An essential role of proneural proteins is to restrict their own activity to single progenitor cells and to inhibit their own expression in adjacent cells, thus preventing these cells from differentiating into neurons. This is achieved in part through a process called lateral inhibition, which involves the evolutionarily conserved Notch signalling pathway.  
"Notch is a transmembrane protein that after binding to ligands encoded by proneural genes undergoes cleavage of its intracellular domain, which is then translocated to the nucleus, where it inhibits expression of proneural genes." 
SOURCE
???
[Huh?] 
"Through this mechanism, proneural gene expression is restricted to single cells that enter a neuronal differentiation pathway, whereas the target cells become committed to a glial fate." 
OK.. so, sounds like Notch gets to 'decide' who will or won't turn into a neuron. [In fact it looks like Notch gets to decide a whole BUNCH of stuff, in an embryo situation. Blows me away that this Notch business was discovered 99 years ago. But I digress.] 

Neural stem cells that Notch has decided won't be neurons are then groomed for glial existence. The radial glia (which are already in there) take on developing the astrocytes, in addition to building scaffolding for cortical layers/columns and guiding cells to their destinations there.. but what are radial glia and where did they come from? P. 21: 
"radial glial cells are generated in the ventricular zone in the early embryo and have several properties similar to those of neuroepithelial cells. In the mammalian brain, most radial glia persist until the late perinatal period and then disappear within weeks or days after birth, when the cells transform into mature astrocytes."
I wonder if radial glia do a similar thing in the spinal cord. There is no cortex in the spinal cord, so maybe not. Here is a hopeful-sounding tidbit to do with radial glia in spinal cords, from 2011.. 
Also, if radial glia disappear, then there must be some other way that astrocytes replenish themselves in adulthood.. but that is a topic we will not concern ourselves with today. 

ANYWAY..
It's good to know about these things, to have become still, for just a moment, and let oneself be mesmerized by this fabulous dance of emergence. Think about it: We are made of stardust, and then some of that dust turns around and becomes star-shaped cells in our heads.. boggles the mind.

But now it's time to move on. 
We must get back to Melzack eventually. 
So, we're back to astroglia and pain. Let's check out that new Nedergaard paper. 

.....

Who is Maiken Nedergaard?
SOURCE
Maiken Nedergaard
Maiken Nedergaard is this phenomenal researcher who runs this lab. She has a whole pile of money to do her work, by the sound of things. She managed to graft human astrocytes into mouse brains and watched the mice be way smarter than mice who had just regular mouse astrocytes. Quite exciting, really. See Forebrain engraftment by human glial progenitor cells enhances synaptic plasticity and learning in adult mice

Here is a list of publications in which she has been involved. [She publishes with Langvin, who stretches connective tissue, which has made her (Langvin) the darling of fascia-loving body-workers..  the relationship seems a bit odd to me; Langvin does not appear to be part of her actual lab, however, as she isn't in any of the personnel lists.] 

Anyway, here is the paper, not even quite out yet, that has me on my tiptoes: Glia and pain: Is chronic pain a gliopathy?

Abstract
Activation of glial cells and neuro-glial interactions are emerging as key mechanisms underlying chronic pain. Accumulating evidence has implicated 3 types of glial cells in the development and maintenance of chronic pain: microglia and astrocytes of the central nervous system (CNS), and satellite glial cells of the dorsal root and trigeminal ganglia. Painful syndromes are associated with different glial activation states: (1) glial reaction (ie, upregulation of glial markers such as IBA1 and glial fibrillary acidic protein (GFAP) and/or morphological changes, including hypertrophy, proliferation, and modifications of glial networks); (2) phosphorylation of mitogen-activated protein kinase signaling pathways; (3) upregulation of adenosine triphosphate and chemokine receptors and hemichannels and downregulation of glutamate transporters; and (4) synthesis and release of glial mediators (eg, cytokines, chemokines, growth factors, and proteases) to the extracellular space. Although widely detected in chronic pain resulting from nerve trauma, inflammation, cancer, and chemotherapy in rodents, and more recently, human immunodeficiency virus-associated neuropathy in human beings, glial reaction (activation state 1) is not thought to mediate pain sensitivity directly. Instead, activation states 2 to 4 have been demonstrated to enhance pain sensitivity via a number of synergistic neuro-glial interactions. Glial mediators have been shown to powerfully modulate excitatory and inhibitory synaptic transmission at presynaptic, postsynaptic, and extrasynaptic sites. Glial activation also occurs in acute pain conditions, and acute opioid treatment activates peripheral glia to mask opioid analgesia. Thus, chronic pain could be a result of "gliopathy," that is, dysregulation of glial functions in the central and peripheral nervous system. In this review, we provide an update on recent advances and discuss remaining questions.

Stay tuned. 
What I hope to learn from this paper is what happens right at the shoreline - right at the zone where peripheral glia meet central glia - Do they talk? Can they talk? is there some sort of chemo-gradient battle fought? Does one usually inhibit the other somehow? If so, how? 

Shorelines are exciting. The planet is full of them and so is the body and so is the nervous system. They are the only place where the edge of one thing is juxtaposed against some other thing. And maybe not every "thing" is always happy in that situation. Out of edges are born emergent processes. 

For pain, the dorsal horn is a preliminary shoreline. Is it a rocky shoreline or is it a nice sloped beach? I mean to find out if I possibly can. 

..........
Previous blogposts

Part 1 First two sentences Part 2 Pain is personal Also Pain is Personal addendum., Neurotags! Pain is Personal, Always.

Part 3a Pain is more than sensation: Backdrop Part 3b Pain is not receptor stimulation Part 3c: Pain depends on everything ever experienced by an individual

Part 4: Pain is a multidimensional experience across time

Part 5: Pain and purpose

Part 6a: Descartes and his era; Part 6b: History of pain - what’s in “Ref 4”?; Part 6c: History of pain, Ref 4, cont.. : There is no pain matrix, only a neuromatrix; Part 6d: History of Pain: Final takedown Part 6e: Pattern theories in the history of pain Part 6f: Evaluation of pain theories Part 6g: History of Pain, the cautionary tale. Part 6h: Gate Control Theory.

Part 7: Gate control theory has stood the test of time: Patrick David Wall;  Part 7bGate control: "The theory was a leap of faith but it was right!"
Part 8: Beyond the gate: Self as mayor Part 8b: 3-ring circus of self Part 8c: Getting objective about subjectivity
Part 9: Phantom pain - in the brain! Part 9b: Dawn of the Neuromatrix model Part 9cNeuromatrix: MORE than just spinal projection areas in thalamus and cortex Part 9d: More about phantom body pain in paraplegics
Part 10: "We don't need a body to feel a body." Part 10b: Conclusion1: The brain generates its own experience of being in a body Part 10c:Conclusion 2: Your brain, not your body, tells you what you're feeling Part 10dConclusion 3: The brain's sense of "Self" can INclude missing parts, or EXclude actual parts, of the biological body Part 10eThe neural network that both comprises and moves "Self" is (only)modified by sensory experience
Part 11We need a new conceptual brain model! Part 11b: Intro to a new conceptual nervous system Part 11c: Older brain models just don't cut it Part 11d: The NEW brain model!
Part 12: Action! 12b: Examining the motor system, first pass. 12c: Motor output and nervous systems - where they EACH came from Part 12d... deeper and deeper into basal ganglia Part 12e: Still awfully deep in basal ganglia Part 12f: Surfacing out of basal ganglia Part 12gThe Action-Neuromatrix 
Part 13: Pain and Neuroplasticity Part 13b: Managing neuroplasticity

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